INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
CITALOHEXAL™ 20 mg FILM-COATED TABLETS

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

CITALOHEXAL™ 20 mg FILM-COATED TABLETS

COMPOSITION
Each film-coated tablet contains citalopram hydrobromide equivalent to 20 mg citalopram.

PHARMACOLOGICAL CLASSIFICATION
A.1.2. Psychoanaleptics (antidepressants).

PHARMACOLOGICAL ACTION
Citalopram is a bicyclic phthallane derivative with antidepressant effect. Its effect is linked to the selective inhibition of specific serotonin (5-HT) reuptake. Citalopram, primarily through its (S)-enantiomer, blocks 5-HT reuptake, leading to potentiation of serotonergic activity in the central nervous system (CNS). Neither citalopram nor its metabolites have an effect on noradrenaline, dopamine and GABA reuptake. Citalopram also has little or no antidopaminergic, antiadrenergic, antiserotonergic, antihistaminergic or anticholinergic properties.
Pharmacokinetics
Oral bioavailability is about 80% with maximum plasma levels being reached in 4 hours (range 1 to 6 hours). Volume of distribution is about 14L/kg (range 9 to 17L/kg). Time to reach steady state concentration is 1 to 2 weeks. Protein binding is about 80%. Elimination half-life is 36 hours (range 28-42 hours).
Citalopram undergoes hepatic metabolism primarily involving the cytochrome P450 (CYP3A4) and 2C19 (CYP2C19) isoenzymes and to a small extent cytochrome P450 2D6 (CYP2D6) isoenzymes. The metabolites inhibit the reuptake of serotonin, but are less potent than the parent molecule.
Citalopram is excreted mainly via the liver with the remainder via the kidneys (approximately 20% of which 12% is unchanged medicine). Longer half-lives and decreased clearance due to a reduced rate of metabolism have been demonstrated in the elderly.

INDICATIONS
CitaloHEXAL is indicated for the treatment of:

•	Depression and prevention of relapse
•	Panic disorders with or without agoraphobia.
•	Obsessive-compulsive disorder (OCD).

CONTRAINDICATIONS

•	Hypersensitivity to citalopram or any of the ingredients in the formulation.
•	Concurrent use with a monoamine oxidase inhibitor (MAOI). At least 14 days should elapse between discontinuing the MAOI and initiating therapy with CitaloHEXAL. MAOIs should not be introduced for 7 days after discontinuation of CitaloHEXAL. (See INTERACTIONS).
•	Severe renal impairment (creatine clearance less than 20 mL/min)
•	Safety and efficacy in pregnancy and lactation has not been established
•	Children under the age of 18 years.(See WARNINGS and SIDE EFFECTS AND SPECIAL PRECAUTIONS).

WARNINGS
CitaloHEXAL should be used with caution in:

•	Elderly patients - Longer half-life and decreased clearance due to a reduced rate of metabolism. A lower dose is recommended in the elderly.
•	Hepatic impairment - Clearance of CitaloHEXAL is reduced. Cautious dosage titration and a lower maximum dose are recommended.
•	Renal impairment - Elimination is decreased. If creatine clearance is less than 20 mL/min CitaloHEXAL should not be used. (See Contra-indications)
•	Seizures or history thereof - There is an increased risk of seizures. CitaloHEXAL should be used with caution in patients with controlled epilepsy and avoided in patients who are poorly controlled epileptics. Care is advised in patients receiving electroconvulsive therapy.
•	Mania or history of mania - Condition may be re-activated. CitaloHEXAL should be discontinued if the patient enters the manic phase.
•	CitaloHEXAL may cause a reduction in heart rate. Caution is advised in patients with a pre-existing slow heart rate.
•	Diabetes mellitus - Rare occurrences of hypoglycaemia have been reported.
•	CitaloHEXAL should not be used with monoamine oxidase inhibitors; imipramine; other serotonergic medicines; moclobemide; alcohol; warfarin; and cimetidine (See Interactions).

Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicine. This risk may persist until significant remission occurs. A causal role, however, for antidepressant medicines in inducing such behaviour has not been established. Patients being treated with CitaloHEXAL should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy, or at any time of dose changes, either increases or decreases.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.
The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia, hypomania and mania. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing CitaloHEXAL, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision is made to discontinue treatment, CitaloHEXAL should be tapered (See PRECAUTIONS and DOSAGE AND DIRECTIONS FOR USE).
Safety and efficacy in children under 18 years of age have not been established. (See CONTRAINDICATIONS and SIDE EFFECTS AND SPECIAL PRECAUTIONS).

INTERACTIONS

•	Monoamine oxidase inhibitors (MAOI) - Concurrent use is contra-indicated.
	Serious and potentially fatal reactions have occurred such as: hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation of vital signs and mental status changes including extreme agitation progressing to delirium and coma. (See CONTRAINDICATIONS)
•	Imipramine - An increase in the concentration of desimipramine (the active metabolite of imipramine) may occur. It appears that CitaloHEXAL does not cause a marked increase in plasma levels of some tricyclic antidepressants.
•	Other serotonergic medicines or medicines with serotonergic activity
	Increased risk of developing the serotonin syndrome, a rare but potentially fatal hyperserotonergic state.
•	Moclobemide - Serotonin syndrome has developed after taking overdoses of moclobemide and CitaloHEXAL.
•	Alcohol - The effects of alcohol may be increased.
•	Warfarin - the anticoagulant activity of warfarin may be increased
•	Cimetidine - the AUC and the maximum plasma concentration of CitaloHEXAL are increased when CitaloHEXAL is administered concurrently with cimetidine

PREGNANCY AND LACTATION
Safety and efficacy in pregnancy and lactation has not been established. CitaloHEXAL is excreted into the breast milk.

DOSAGE AND DIRECTIONS FOR USE
Depression
20 mg a day as a single dose. Dosage may be increased by 20 mg a day at intervals of at least one week to a maximum of 60 mg depending on the patient’s response.
Panic Disorder
10 mg a day as a single dose for the first week then increasing to 20 mg a day. The dose may be increased thereafter as required to a maximum of60 mg a day depending on the patient's response.
Obsessive Compulsive Disorder
20 mg a day as a single dose. This dose can be increased by 20 mg increments to a maximum of 60 mg a day depending on the patient's response.
Special populations
Elderly: 20 mg a day as a single dose. Depending on the patient's response, the dose can be increased to a maximum of 30 mg a day.
Reduced hepatic function: dose should be halved.
Reduced renal function: Dose adjustment is not necessary in cases of mild or moderate renal impairment.
The onset of action is seen within 2 to 4 weeks. Treatment should be continued for an appropriate length of time (up to six months) after recovery in order to prevent relapse. The medicine should be gradually withdrawn during a couple of weeks when stopping therapy,(See SIDE EFFECTS AND SPECIAL PRECAUTIONS.)
CitaloHEXAL may be taken with or without food in the morning or evening.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects:
Cardiovascular system:

•	Frequent: Palpitations, tremor
•	Less frequent: Bradycardia

Central nervous system:

•	Frequent: Sleep disturbances, paraethesia, restlessness, somnolence, headache, dizziness, fatigue
•	Less frequent: Agitation, confusion, impaired concentration, malaise, mania, convulsions, serotonin syndrome, neuroleptic malignant syndrome

Endocrine/Metabolic;

•	Frequent: Weight changes

Gastrointestinal:

•	Frequent: Nausea, constipation, diarrhoea, dyspepsia, dry mouth
•	Less frequent: Salivation

Kidney/Genitourinary:

•	Frequent: Micturition disorders
•	Less frequent: Sexual dysfunction including ejaculation disorder, decreased libido, anorgasmia

Liver:

•	Less frequent: Hepatitis

Musculoskeletal:
•Frequent: Asthenia
Ocular:

•	Frequent: Accommodation disturbances
•	Less frequent: Mydriasis

Respiratory:

•	Less frequent: Nasal congestion

Skin:

•	Frequent: Sweating
•	Less frequent: Rash

Other:

•	Less frequent: Yawning
•	Hostility, suicidal ideation and self harm have been reported in children.

Special precautions:

•	Patients should be monitored during early therapy until improvement in depression is observed because suicide is an inherent risk in depressed patients.
•	CitaloHEXAL may impair performance of skilled tasks. If affected these patients should not operate machinery or drive.
•	Serotonin syndrome is more likely to occur after an increase in dose.
•	If therapy with CitaloHEXAL is to be discontinued, it is recommended that the dose is decreased gradually in order to prevent the possibility of a withdrawal syndrome.
•	Avoid alcohol. (SEE INTERACTIONS)
•	Safety and efficacy in children under 18 years of age have not been established. In clinical trials in Major Depressive Disorder, there were increased reports of hostility and suicide - related adverse events such as suicidal ideation and self- harm.
•	Abrupt discontinuation of the product can lead to discontinuation effects which include disequilibrium, nausea, vomiting, fatigue, lethargy, sleep disturbances, agitation and irritability.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE EFFECTS AND SPECIAL PRECAUTIONS)
Symptoms of overdose: Tiredness, weakness, sedation, dizziness, tremor, nausea, somnolence and sinus tachycardia.
Treatment of overdose:
Treatment is symptomatic and supportive.
There is no specific antidote to CitaloHEXAL.
The stomach should be emptied as soon as possible by emesis or gastric lavage. Monitoring of cardiac and vital signs necessary and medical surveillance is advisable for about 24 hours.

IDENTIFICATION
White, oblong, biconvex film coated tablets with a one sided notch and embossment C20.

PRESENTATION
Clear PVC/aluminium blister strips containing 10 tablets each.
3 (10) blister strips to be packed into a carton i.e. 30 tablets per carton
OR
Clear PVDC coated PVC / aluminium blister strips containing 10 tablets each.
3 (10) blister strips to be packed into a carton i.e. 30 tablets per carton.

STORAGE
Store below 25°C.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER
36/1.2/0518

NAME AND BUSINESS ADDRESS OF APPLICANT
HEXAL Pharma (SA) (Pty) Ltd
46 Mahogany Road
Mahogany Ridge
Pinetown
3610

DATE PUBLICATION OF PACKAGE INSERT
March 2005

New addition to this site: April 2005
Source: Pharmaceutical Industry
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